SCOPING DOCUMENTS - hbm4eu.eu€¦ · PFASs bind to proteins and partition to phospholipids. ... and reduced fertility among offspring as a result of early life exposures (Halldorsson

HORIZON2020 Programme Contract No. 733032 HBM4EU

SCOPING DOCUMENTS

(1st

round of prioritization)

Prioritized substance group: PFAS

Chemical Group leader: Maria Uhl

Authors:

Maria Uhl, Thorhallur Ingi Halldorsson, Ingrid Hauzenberger, Christina

Hartmann

Co-authors : Xenia Trier, Tony Fletcher, Philippe Grandjean, Marqués Bueno

Montserrat, Wang Zhanjun

Date:

[2]

2017-12-04 Document version:3

[1]

Table of contents

1. Introduction .............................................................................................................................. 2

2. Background Information ........................................................................................................... 3

3. Categorization of Substances .................................................................................................. 3

4. Policy-related questions ......................................................................................................... 25

5. Research Activities to be undertaken ..................................................................................... 26

6. Results Report ....................................................................................................................... 30

7. References ............................................................................................................................ 31

[2]

1. Introduction

HBM4EU has established Chemical Working Groups during the proposal phase for the nine

prioritized substance groups that HBM4EU will work on in 2017 and 2018. Additional substance

groups will be identified by late 2018 through the implementation of a refined prioritization strategy.

For each substance group, scoping documents are produced under Workpackage 4.4 of HBM4EU.

The scoping document will contain a review of the available evidence, will list policy-related

questions, identify knowledge gaps and propose research activities. Proposed activities will be fed

into the framework of work packages and tasks of HBM4EU in a coordinated and harmonized

manner, and will constitute the basis for the annual work plans. The scoping documents are the

linkage between policy questions and the research to be undertaken (broken down for single

substances) in order to answer those questions. This methodology will optimize work on the

different substances, avoid redundancies, ensure coordination and facilitate the calculation of

budgets for each WP. The scoping documents do not contain a comprehensive literature review

per substance group but are intended to provide information for the WP leaders who will draft the

Annual Work Plans.

For the selected substance groups the availability of (toxicology or human biomarker) data is

variable. A scheme was therefore developed to classify the compounds within each substance

group into categories A, B, C, D and E based on the availability of data to answer research

questions (see further). In direct response to the key project goal of exploiting HBM data in policy

making to positively impact on human health, the research activities for each substance group will

generate knowledge on exposure trends and associated health effects. Throughout the course of

the project, we will generate knowledge that will shift substances towards to a higher level of

knowledge category.

For further information see www.hbm4eu.eu

http://www.hbm4eu.eu/

[3]

Template for Scoping document

Substance group: PFAS

2. Background Information

Introduction

Per- and polyfluoroalkyl substances (PFASs) have been in use since the 1950ies as ingredients of

intermediates of surfactants and surface protectors for assorted industrial and consumer

applications. Within the past decade, several long-chain perfluoroalkyl acids have been recognized

as extremely persistent, bioaccumulative and toxic. Many have been detected globally in the

environment, biota, food items, and in humans (OECD, 2015). It has been recognised more

recently that shorter chain PFASs increasingly used as alternatives are also very persistent and

thus very mobile in the environment, presumably leading to ground water contamination in future.

To date many known and unknown alternatives of the so far regulated PFASs are used worldwide

leading to environmental contamination und increasing human body burdens.

Hazardous properties

PFASs bind to proteins and partition to phospholipids. The elimination kinetics are highly species

dependent, with humans showing the longest half-lives of up to e.g. 8.5 years for perfluorohexane

sulfonic acid (PFHxS). A recent publication reports an estimated elimination range of 10.1 to 56.4

years – median 15.3 years for chlorinated polyfluoroalkyl ether sulfonic acids [Cl-PFESAs] (Shi et

al., 2016). The CLP human health hazard classifications of the different substances are depicted in

table 1. Substances which are best-known – perfluorooctane sulfonate (PFOS) and

perfluorooctanoic acid (PFOA) – are classified as carcinogenic (Carc. 2, suspected human

carcinogens, such as kidney and testicular), toxic for reproduction (Repr. 1B, presumed human

reproductive toxicants; Lact., may cause harm to breast-fed children), toxic to specific target

organs (STOT RE 1, specific target organ toxicity – repeated exposure) and acute toxic (Acute

Tox. 3-4) for different exposure routes. PFOS and PFOA belong to the so called long-chain

perfluorinated compounds, which refers to perfluorocarboxylic acids with carbon chain lengths of 8

and higher, including PFOA; perfluoroalkyl sulfonates with carbon chain lengths of 6 and higher,

including PFHxS and PFOS; and precursors of these substances that may be produced or may be

present in products. A recent report showed that in product samples the detected individual PFAS

constituted only a very minor part of the total organic fluorine (TOF), illustrating large data gaps in

the current knowledge which PFASs that are being used in these products (Borg, 2017).

Several long-chain compounds beside PFOS and PFOA have also been identified as toxic to

reproduction; further endpoints concern carcinogenicity, liver toxicity, neurotoxicity and

immunotoxicity. Whether numerous other non-regulated PFASs show similar toxicity is currently

less well established. In many cases data availability is poor and therefore no classification is

possible. However, persistence is assumed to concerns largely all PFASs by reason of the

extreme strength and stability of the carbon-fluorine bonds.

[4]

For PFOS and PFOA adverse effects on thyroid metabolism and lipid metabolism have been

reported in a multitude of epidemiological studies suggesting endocrine disrupting potential (Barry

et al., 2013).

Additional concerns include increased risk of miscarriage, reduced birth weight, increased weight

in adult life, and reduced fertility among offspring as a result of early life exposures (Halldorsson et

al., 2012; Jensen et al., 2015; Joensen et al., 2013; Timmermann et al., 2014). Postnatal

exposures have also been associated with thyroid hormone imbalances and reduced immune

response to vaccination (Grandjean and Budtz-Jørgensen, 2013). The US National Toxicology

programme has listed both, PFOA and PFOS, as presumed to be an immune hazard to humans

(NTP, 2016).

Grandjean and Clapp (2015) documented carcinogenicity, immunotoxicity and developmental

toxicity of PFOA and highlighted the endocrine disrupting effects. A recent publication describes

prenatal exposure to perfluoroalkyl substances and reduction in anogenital distance in girls at 3

months of age in a Danish mother-child cohort (Lind et al., 2017).

A recent systematic review on health effects of PFAS exposure and childhood health outcome

observed generally consistent evidence for PFAS’ association with dyslipidemia, immunity

including vaccine response and asthma, renal function, and age at menarche (Rapazzo et al.,

2017).

A comparison of birth outcomes in a PFAS contaminated region in italy with a less exposed

population group showed a significantly increased risk for gestational diabetes, preeclampsia and

small size for gestational age. Further biomonitoring data would be needed to confirm direct cause

and effect (WHO, 2015).

Long chain PFASs (certainly PFOA, PFOS & PFHxS, and possibly others) are actively reabsorbed

in the kidney and intestine. This active reabsorption varies and the determinants of the variation

(e.g. renal function) may a) be a confounder in using serum levels as the exposure marker in

analysing health effects, b) may make individuals more or less vulnerable to the adverse health

effects and thus affect how health based limits are set, or c) may be a basis for identifying

subgroups at extra risk.

Since PFOS and PFOA can still be measured in highest concentrations in biota and in humans,

exerting similar toxic effects along with and similar to a range of long-chain PFASs measured in

blood, together with a range of unidentified PFASs the possibility of mixture effects is very high.

Policy relevance

Current regulatory actions within the European Union and elsewhere mainly concern PFOS and its

derivatives (POP regulation, Commission Regulation (EU) No 757/2010) and PFOA and PFOA-

related substances which are currently under review as global POPs under the UNEP-Stockholm

Convention. PFOA and related substances are subject of a restriction of the manufacturing,

marketing and use (EU 2017/1000). Certain per- and polyfluorinated substances can be degraded

to persistent perfluorinated substances like PFOS or PFOA under environmental conditions or in

humans and are therefore precursors. OECD (2007) lists e.g. 165 PFOS related substances

including derivatives and polymers of perfluorooctane sulfonate, perfluorooctane sulfonamide and

perfluorooctane sulfonyl chemicals. Additional identities of PFOS- and PFOA-related substances

can be found in ECHA (2014), Buck et al. (2011), Environment & Health Canada (2012), OECD

(2011) or U.S. EPA (2006). The OECD is currently updating its Lists of (PFOS), Perfluoroalkyl

Sulfonic Acids (PFSAS), PFOA, Perfluorocarboxylic Acids (PFCAs), related compounds and

chemicals that may degrade to PFCAs. The publication of the updated lists and results is planned

[5]

for December 2017. With the current regulations on PFOS and PFOA also these precursor

substances are subject to the EU restrictions.

Another restriction proposal for long-chain PFCAs covering perfluorononan-1-oic acid (PFNA),

nonadecafluorodecanoic acid (PFDA), henicosafluoroundecanoic acid (PFUnDA),

tricosafluorododecanoic acid (PFDoDA), pentacosafluorotridecanoic acid (PFTrDA),

heptacosafluorotetradecanoic acid (PFTDA), including their salts and precursors was submitted to

ECHA mid 2017 (Germany, 2017). Several long-chain PFASs are also on the Candidate List of

substances of very high concern (SVHC) under REACH: PFDA and its sodium and ammonium

salts (Reprotox. (57c) and PBT (57d)), nonadecafluorodecanoic acid, decanoic acid,

nonadecafluoro-, sodium salt, ammonium nonadecafluorodecanoate, perfluorononan-1-oic-acid

and its sodium and ammonium salts (Reprotox (57c)), perfluorononan-1-oic-acid, sodium salts of

perfluorononan-1-oic-acid, ammonium salts of perfluorononan-1-oic-acid, ammonium

pentadecafluorooctanoate (APFO) (Reprotox. (57c) and PBT (57d)), henicosafluoroundecanoic

acid (C11-PFCA) (vPvB (57e)), and heptacosafluorotetradecanoic acid (C14-PFCA) (vPvB (57e)).

Other widely used substances are still under substance evaluation or are foreseen to be regulated

under REACH, such as PFSAs (PFHxS, PFBS), ADONA, 6:2 FTMA and several short-chain

PFCAs (C4-C7). For Cat A-C substances, regulatory actions are depicted in table 1.

Further (regulatory) activities, which have been highlighted as necessary but not yet sufficiently

covered, should address fluoropolymers and fluoroethers, including monitoring to support the

ongoing regulatory work (Pelthola-Thies, 2017). According to KEMI (2015) less than 2 percent of

the 3,000 on the global market available PFAS are registered under REACH.

The current workplan for regulatory activities of PFASs under REACH/CLP proposed by ECHA is a

group–wise as well as an arrow head approach. Aim is to identify the precursors of the respective

“arrow head” substance which is the terminal degradation product that is object of the regulatory

action which should cover the precursors – and group of precursors already identified. According to

ECHA is additional work at a more generic level needed considering the high amount of precursor

types. Further information on PFASs from imported articles is needed as well as work on

fluoropolymers and fluoroethers to clarify if those can be perceived as PFASs precursors (Pelthola-

Thies, 2017).

PFASs are also relevant within the remit of the European Food Safety Authority (EFSA): (in food

contact materials and food flavourings on one hand and food contaminants on the other). Recently,

EFSA has been asked to prepare an opinion on the human health risks of the presence of PFASs

in food. First results are expected in the end of 2017; preliminary results suggest that from the 27

substances under investigation refined chronic dietary exposure estimates can only be calculated

for 11 substances. To date, it is not known for which compounds sufficient documentation,

including reliable modelling results, will be available to derive health-based guidance values

(Johanson, 2017). Various PFASs are used as food contact materials (FCM) and also as

flavouring in food, e.g. one of the flavourings currently approved unter Regulation No 1334/2008 is

a polyfluorinated organic chemical (FL16.119, N-(2-methylcyclohexyl)-2,3,4,5,6-

pentafluorobenzamide).

There are voluntary agreements with industry in Canada or the USA to phase out PFASs C8

chemistry like the U.S. EPA Stewardship Programme1.

PFASs have been recognized as an issue for concern under SAICM (Strategic International

Approach to International Chemicals Management)2. The OECD has established a web portal in

order to facilitate information exchange among stakeholders3.

1 http://epa.gov/oppt/pfoa/pubs/stewardship/index.html

http://epa.gov/oppt/pfoa/pubs/stewardship/index.html

[6]

Exposure characteristics

Trends in production volume/environmental concentrations

A minor part of the family of PFASs are perfluoroalkyl acids (PFAA), perfluoroalkylcarboxylic acids

(PFCA), perfluoroalkane sulfonic acids (PFSA), compounds derived from perfluoroalkane sulfonyl

fluoride (PASF), fluorotelomer (FT)-based compounds and per- and polyfluoroalkylether (PFPE)-

based compounds. Another presumably major part are polymers (fluoropolymers (FPs), side-chain

fluorinated polymers and perfluorpolyethers (PFPEs) (OECD, 2013). According to KEMI (2017)

there are 2,817 PFASs on the market. For only 15 % of them adequate data are available;

whereas for 40% data are missing (KEMI, 2017). Many fluorinated substances enter the EU

through the import of articles (e.g. textiles) and for the most part these are not monitored (KEMI,

2015) providing an indirect exposure source. The lack of data concerns identification, use and

exposure beside from toxicity and ecotoxicity. Among the new chemical groups, fluoro silicones,

perfluoro polyethers and perfluoro alkanes are under discussion. Recent uses comprise

surfactants, repellents, uses in textiles and in leather, paper and electronic industry, cosmetics,

pesticides, lubricants, pharmaceuticals and printing (Fischer, 2017). For the large group of

polymers no data are available at all, as polymers are not covered within REACH. However, there

are concerns from the scientific point of view that at least some groups of polymers may also be

degraded into persistent PFASs. For example fluorinated side-chains can be lost through ageing

and environmental conditions.

Environmental behaviour: half-lives in environment/ transport

Perfluoroalkyl and perfluoroether moieties of PFASs are highly persistent under environmental

conditions. All PFASs ultimately degrade into highly persistent end products. PFASs are

ubiquitously detected in the environment. Contamination of the drinking water resources as

environmental health thread has been reported for PFASs e.g from the Veneto Region in Italy

(WHO, 2017) but also from Sweden (Banzhaf et al, 2017) and other European countries. Whereas

most data are available for the small group of long-chain PFASs, non-reversible environmental

exposure has to be considered for a by far larger group. Recent data demonstrate considerable

exposure of alternatives such as GenX in the drinking water (e.g. Gebbink et al., 2017).

There are also concerns about short-chain PFASs, which are assumed to be less bioaccumulative

but very persistent and mobile contaminants found in drinking water and food, including vegetables

(Hedlund, 2016, Danish EPA, 2015).

Human-related exposure sources and uses, human exposure routes

Humans can be exposed directly (via diet, drinking water, consumer products, etc.) and indirectly

through transformation of «precursor substances» such as polyfluoroalkyl phosphate esters

(PAPs), fluorotelomer alcohols (FTOHs), fluorotelomer iodides (FTIs) and fluorotelomer acrylate

monomers (FTAcs). These fluorotelomer-based substances biotransform to yield PFCAs, yet also

form bioactive intermediate metabolites, which have been observed to be more toxic than their

corresponding PFCAs (e.g. Rand et al., 2017).The precursor contribution to PFASs daily

exposures was recently estimated for a high exposure scenario to contribute up to >50% to

individual PFCAs like PFOA or PFDA, whereas it is considerable lower up to 10% for e.g. PFOS

for a low exposure scenario (Gebbink et al., 2015).

Human biomonitoring (HBM) data availability

2 http://www.saicm.org/EmergingPolicyIssues/Perfluorinatednbsp;Chemicals/tabid/5478/language/en-US/Default.aspx

3 http://www.oecd.org/ehs/pfc/#Purpose_of_Web_Portal

http://www.saicm.org/EmergingPolicyIssues/Perfluorinatednbsp;Chemicals/tabid/5478/language/en-US/Default.aspx

http://www.oecd.org/ehs/pfc/#Purpose_of_Web_Portal

[7]

Human exposures to PFASs have been reported in numerous studies in Europe and worldwide.

Most of these studies were focused on blood or breast milk concentrations of PFOS and PFOA,

while others also included PFBS, PFHxS, PFDS, PFBA, PFPeA, PFHxA, PFHpA, PFNA, PFDA,

PFUdA, PFDoA, PFTrDA, PFTeDA, FOSA, MeFOSA, N-EtFOSA, N-EtFOSAA and diPAP.

Contrary, human exposure to e.g. 8:2 diPAP, 6:2 diPAP, 8:2 PAP, 6:2 PAP, PFDPA, PFOPA,

PFHxPA or ADONA has been addressed to a small extent only; the majority of new fluorinated

compounds that enter the market as replacements has not been measured in human matrices yet.

Concerning PFOS the effectiveness evaluation under the UNEP Stockholm Convention concluded

that for human matrices from Western Europe, Canada, Australia and Asia-Pacific countries levels

seem gradually declining. Although PFOS is measured at low concentrations in human breast milk

and is detected in higher concentrations in human blood, there are good correlations between the

measurement results in these two matrices (UNEP, 2016).

In several studies time trends of PFAS exposure in European countries were investigated.

According to Axmon et al. (2014) investigating plasma samples from 1987-2007 in Sweden there

was a peak in PFOS and PFOA blood concentrations around 2000 and increasing PFHxS, PFNA,

PFDA and PFUnDA concentrations within the overall study period. Also Glynn et al. (2012)

reported increasing concentrations of PFBS, PFHxS, PFNA and PFDA in Swedish breast milk

samples between 1996 and 2010. This is also in line with the study from Gebbink et al. (2015)

reporting increasing trends in pooled serum samples from Sweden for PFHxS, PFNA, PFDA,

PFUnDA, PFODA and PFTrDA. Analyses of serum samples from Norway from 1979 to 2007

documented decreasing concentrations of PFOS and PFOA from 2001 onwards, whereas PFNA,

PFDA, PFUnDA were increasing, and for PfHxS and PfHpS no trend could be observed (Nøst et

al., 2014). In Denmark, concentrations of seven PFASs (PfHXS, PfHpS, PFOS, PFOA, PfNA,

PfDA, PfUnDA) decreased in the period 2008-2013 (Bjerregaard-Olsen et al., 2016). Schröter-

Kermani et al. (2013) reported decreasing concentrations from 2001 onwards for PFOS, from 2008

for PFOA and from 2005 for PfHxS and stable concentrations for PFNA in samples from Germany

from 1982 to 2010. Also Yeung et al. (2013a, 2013b) observed decreasing concentrations for

PFOA after 2000, and increasing concentrations for PFNA, PFDA and PFUnDA. No significant

trend was observed for PFHXS and 8:2 di-PAPs. Isomer profiling of perfluorinated substances can

be used as a tool for source tracking. Depending on the two production processes i.e.

electrochemical fluorination (ECF) or telomerisation different PFAS isomers are produced.

Branched isomers of PFAS are mainly manufactured by the ECF method, which has historically

been applied to produce PFOS and PFOA. The differing properties of linear and branched PFAS

isomers can affect their fate, behavior and toxicokinetics. So the structural isomer patterns of

PFOA and PFOS in humans may be useful for understanding routes and recent or historic sources

of exposure (Benskin et al. 2010). Beeson et al. (2011) showed that branched isomers crossed the

placenta more efficiently than did linear PFOS and PFOA isomers. Interesting results stem from

autopsy analyses: Bioaccumulation occurs in different tissues to a different extent, e.g the short

chain perfluorobutanoic acid (PFBA) accumulates predominantly in kidney and lung: 304 ng/g (to a

~10-fold higher concentration than PFOA) in the lungs and 464 ng/g (~230-fold higher

concentration compared with PFOA) in the kidneys (Danish EPA, 2015).

There are major knowledge gaps on fluorinated alternatives currently used by industry; these

knowledge gaps concern production volumes, use, fate and behaviour, and toxicity (Danish EPA,

2013; Wang et al., 2013, 2016, 2017). Known fluorinated alternatives can be categorized into two

groups, namely [i] shorter-chain homologues of long-chain PFAAs and their precursors, and [ii]

functionalized perfluoropolyethers (PFPEs), in particular perfluoroether carboxylic and sulfonic

acids (PFECAs such as ADONA and GenX and PFESAs such as F-53 and F-53B) (Wang et al.,

2015). Perfluoroalkyl phosphonic and phosphinic acids are also used as alternatives in certain

applications. PFPAs are likely to be persistent and long-range transportable, whereas PFPiAs may

be transformed to PFPAs and possibly PFCAs in the environment and in biota (Wang et al., 2016).

[8]

In environmental samples fluorotelomer-based substances were identified as the most relevant

precursors of PFCAs based on the frequency of detection and the concentration of FTOHs,

biotransformation intermediates (e.g. FTUCAs and FTCAs) and persistent biotransformation

products (e.g. x:3 acids and PFCAs) (UBA, 2016).

Health based guidance values available for HBM data

In the REACH restriction dossier on PFOA internal DNELS4 were derived based on different

endpoints in animal and human studies. The respective values derived for the general population

were in the range of 0.3 ng/ml and 277 ng/ml (ECHA, 2014). The Committee for Risk Assessment

(RAC) of the European Chemicals Agency (ECHA) has finally derived a DNEL of 800 ng/ml for the

general population, arguing that a DNEL cannot be reliably derived from some effects (e.g. on the

mammary gland) that may be more sensitive than the animal data currently used in the risk

characterisation, as these data are not robust enough (ECHA ,2015). The German Human

Biomonitoring Commission has published a re-assessment of the HBM-values of PFOS and PFOA

in 2016. The HBM-I-value represents the concentration of a substance in human biological material

below which no risk for adverse health effects over life time is expected (HBM Commission, 2014).

The respective HBM-I-values are 2 ng PFOA/ml and 5 ng PFOS/ml blood plasma (HBM

Commission, 2016). The HBM Commission has decided to use the existing POD ranges of 1 to 10

ng/ml as a basis and selected 2 ng/ml comprising the HBM-I-value for PFOA, pointing to the

consistency of results from animal and epidemiological studies.

Within the scientific community discussions on the most sensitive health endpoints are still

ongoing, effects on immune system and on cholesterol levels might occur at even lower exposure

concentrations. Results of the ongoing EFSA assessment are expected in early 2018.

Technical aspects

Biomarkers available for parent compounds or metabolites in human matrices, and main

characteristics of analytical methods (quantitative, semi-quantitative…)

Analytical targets for the analysis in biomonitoring studies can include the parent compound, its

metabolite(s) and transformation product(s) or other chemical products formed in the body or the

environment. Known PFASs were mostly analysed by high performance liquid chromatography

coupled with tadem mass-spectrometry (HPLC-MS/MS). FTOH and FTOH precursors (FTMAC

and PAPs) and their metabolites can be measured by targeted methods, by low or high resolution

mass spectrometry. Methods for possibly cationic PFASs (such as betaines used e.g. in firefighting

foams) can be analysed using specific methods used for environmental matrices. Analyses of

FTMAC require derivatisation, followed by gas chromatography coupled with mass-spectrometry

(GC-MS) analysis (Place and Field, 2012; Trier, pers. comm., 2017). In recent years, several

studies on total fluorine (TF), inorganic fluorine (IF), exactable organic fluorine (EOF) and specific

known PFASs in environmental and blood samples were conducted. Usually, TF, IF and EOF were

fractionated and measured by combustion ion chromatography (CIC). It has been shown that

PFOS was still the dominant PFAS contributing up to 90% to known PFASs in 30 blood samples

sampled in three Chinese cities in 2004. PFOS, PFHxS, PFOSA, PFDoDA, PFUnDA, PFDA,

PFNA, PFOA, PFHpA, PFHxA contributed 33 to 85% to total EOF (Yeung et al., 2008). In 2016,

Yeung and Mabury (2016) investigated blood samples from China and Germany to identify

concentrations of EOF and 52 specific PFASs including including PFSAs, PFCAs, PFPAs,

PFPiAs, FTSAa, PAPs, FTCAs/FTUCAs, di-SAmPAPs, FASAs, FOSAA and N-alkyl-FOSAAs.

PFSAs represented the majority of EOF with decreasing contribution: 70% in 1982, 60% in 2003,

4 DNEL: Derived No Effect Level:

[9]

25% in 2009. Mass balance analysis between EOF, which provides an estimate of all fluorinated

substances, and known quantifiable PFASs in human blood samples have shown the presence of

unidentified organofluorides up to 80%. These findings suggest that other PFASs (e.g. precursor or

intermediate compounds) might be significantly important (Yeung and Mabury, 2016). A detailed

description of the study results can be found elsewhere (Miyake et al., 2007; Yeung et al,. 2008;

2009, Yeung and Mabury 2016)

However, these methods may not allow distinguishing between PFASs exposure and fluorine

based medication. This concern is particularly related to the fact that many pharmaceuticals may

contain fluorinated moieties to make them more persistent in human bodies (Wang, pers. Comm.,

2017).

In best of our knowledge, it is not feasible and reasonable to measure all relevant PFAA precursors

due to a lack of an overview on which precursors are being produced and used and to which ones

humans are exposed to at the moment. Considering that most precursors would be transformed

into acids in human body, it would be an interesting approach to measure the “total oxidisable

precursors” in human matrices. The “total oxidisable precursors” methods have been used to

reflect the total exposure to PFAAs and PFAA precursors in a number of environmental samples.

Due to its nature of radical reactions with a large, complex mixture, the methods may not easily or

never be standardised and the results may not be reproducible. However, it might be a semi-

quantitative indicator to demonstrate PFAAs exposure stemming from the variety of precursors

(Wang, pers. Comm., 2017).

Further analytical methods to simultaneously analyse as many PFASs as possible should be

developed (Wang et al., 2016).

Societal concern

PFASs are widely used in society and be as a whole group a cause for concern. Individual PFASs

or their degradation products are extremely persistent in the environment and is has been shown

that several of them are very mobile, bioaccumulative and toxic, whereas for several others there is

only some indication as scientific proof is lacking at present. Nevertheless, many PFASs, including

fluorinated alternatives to long-chain PFASs, can be ubiquitously detected in the biotic and abiotic

environment, in wildlife and in humans, even in remote regions such as the Arctic since several

years. In several countries PFASs have been found in ground and drinking water (Domingo et al.,

2012; KEMI, 2017). Currently, there are several contamination cases known in different countries

(e.g. in Germany, Sweden, Italy, Spain and The Netherlands). It can be assumed that also in the

majority of the European and associated countries PFASs contamination in certain areas is a so

far unidentified issue. In early 2017, an news alert has been published in Science for Environment

Policy titled “Europe's rivers ‘highly contaminated’ with long-chain perfluoroalkyl acids”, stating that

all large European rivers are highly contaminated with perfluoroalkyl acids and further, that

European environmental quality standards for PFOS are exceeded in all of them (EC, 2017).

Recently, the PFOA replacement chemical GenX was detected at all downstream river sampling

sites with the highest concentration (812 ng/L) at the first sampling location downstream from a

fluorochemical production plant, which was 13 times higher than concentrations of sum

perfluoroalkylcarboxylic acids and perfluoroalkanesulfonates (∑PFCA+∑PFSA) (Gebbink et al.,

2017). Furthermore, there is a strong indication that PFASs are increasingly used in chemical

products, processes and articles, and that they are more and more detected in various

environmental matrices. The knowledge about their specific uses and therefore the sources of

emissions as well as hazard and risk is poor for many of the substances in this group (KEMI,

2017). Especially very limited knowledge in the public domain on the structures, properties, uses

and toxicological profiles of fluorinated alternatives is available. The levels of some fluorinated

[10]

alternatives or their degradation products, such as perfluorobutane sulfonic acid (PFBS) or

perfluorobutanoic acid (PFBA), have been shown to be rising in the environment and human

tissues in recent years in Europe (Scheringer et al., 2014). Fluorotelomer market size estimations

predict increasing demands globally as well as a rise in the consumption as shown by Global

Market Insights (2016). The number of approved patents in the US with “perfluor” in the patent text

has raised to more than 400 per month (Fischer, 2017).

One of the major societal concerns is the irreversibility of contamination, together with endocrine

disrupting effects, carcinogenicity, toxicity to reproduction, effects on immune system and on lipid

metabolism for a broad range of PFASs.

A recent briefing provided by Chemtrust points out that children are currently not sufficiently being

protected from chemicals that can disrupt brain development; they list per- and polyfluorinated

compounds as one of the chemicals substance groups of concern (Chemtrust, 2017a). Chemtrust

also raises the issue of use of PFASs as food contact materials and refers to a report on the

implementation of the Food Contact Materials Regulation of the European Parliament which states

that action at EU level is needed to address the lack of EU specific measures and the gaps in risk

assessment, traceability, compliance and control (EU parliament, 2016) and an assessment of the

Joint Research Center on the regulatory and market situation of the non-harmonised food contact

materials in the EU (Simoneau et al., 2016). Also, European consumer organisations call for action

on fluorinated compounds in fast food packaging (BEUC, 2017).

Moreover the Europen Environmental Bureau (EEB) addressed concerns on exposure of humans

to the big group of PFASs: “We would like HBM4EU to address in particular the lack of human

exposure information on the substances of the group that are being used as alternatives to other

substances of the group that are under regulatory activity, such a PFOS and PFOA” (EEB, 2017).

According to the EEA, PFASs contamination has the potential of a planetary boundary threat

(Trier, 2017).

[11]

3. Categorization of Substances

Based on the huge amount of available PFAS on the market and the knowledge gaps on identity,

toxicity and uses (of the alternatives), the listing of chemicals in categories A-E is an attempt to

categorize possibly relevant substances that contribute to the overall PFAS burden in humans.

Several substances are listed in category A due to their restriction as PFOS- and PFOA-related

substances, although limited or no HBM data are available. Efforts should be made to improve the

methods to detect the broader spectrum of Category A substances. However, the priority for future

HBM research should cover PFOS and PFOA alternatives with high production volume, wide

dispersive use and identified or suspected hazardous properties which qualifies for SVHC

identification. For substance selection the following issues were considered: availability of

substance identity and literature, building blocks or alternative processing aid in polymer

manufacturing, use as food contact material, alternatives to long-chain PFAS and degradation

products/intermediates. Due to the variety of PFAS classes and structures it is clear that the list of

substances in categories C-E is open ended and should regularly be updated.

Table 1: Substances included in the substance group, listed according to availability of toxicology

and human biomarker data, in category A, B, C,D, E substances (see general introduction)

Category Abbreviation/

Acronym

Systematic name CAS No. Regulation

A

PFOA Perfluorooctanoic acid (linear

and branched isomers) 335-67-1

REACH Annex XVII

restriction (Regulation (EU)

2017/1000)5, SVHC

Candidate List (PBT, Repr.),

CLH (Carc. 2, Repr. 1B,

STOT RE 1, Acute Tox. 4,

Eye Dam. 1), proposed for

inlcusion in the Stockholm

Convention, Norman 2011,

sufficient EU HBM data

available

PFOS

Perfluorooctane sulphonate,

Heptadecafluorooctane-1-

sulphonic acid (linear and

branched isomers)

1763-23-1

REACH Annex XVII

restriction, CLH (Carc. 2,

Repr. 1B, Lact., STOT RE 1,

Acute Tox. 4, Aquatic Chron.

2), PIC regulation, POP

Regulation (EG) No.

757/2010, Stockholm

Convention, environmental

legislation (Seveso, Directive

2012/18/EU; Regulation

649/2012 concerning export

and import of hazardous

chemicals), sufficient EU

5 http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A32017R1000

http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A32017R1000

[12]

HBM data available

PFNA perfluoro-n-nonanoic acid 375-95-1

Restriction proposal6, CLH

(Carc. 2, Lact., STOT RE 1,

Repr. 1B, Acute Tox. 4, Eye

Dam. 1), SVHC Candidate

List (Repr., PBT), PACT list

(CMR, PBT), Annex III

Directive 2008/98/EC on

waste, Norman 2011, EU

HBM data available

PFDA perfluoro-n-decanoic acid 335-76-2

Restriction proposal, SVHC

Candidate list (PBT, Repr.),

PACT list (PBT), Norman

2011, EU HBM data

available

PFU(n)DA perfluoro-n-undecanoic acid 2058-94-8


Candidate List (vPvB), self

classification (Acute tox. 4,

Skin irrit. 2, Eye irrit. 2,

STOT SE 3), Norman 2011,

EU HBM data available

PFDoDA Perfluorodeconaoic Acid 307-55-1



classification (Skin irrit. 2,

Eye irrit. 2, STOT SE 3,

Metal corr. 1, Skin corr. 1B,

Eye dam. 1), Norman 2011,


PFTrDA perfluoro-n-tridecanoic acid

72629-94-8 Restriction proposal, SVHC


classification (Skin corr. 1B),


PFTeDA perfluoro-n-tetradecanoic acid 376-06-7

SVHC Candidate List

(vPvB), Restriction proposal,

Norman 2011, EU HBM data

available

PFHxS perfluoro-1-hexanesulfonate

(linear and branched isomers)

355-46-4

PACT list, proposed for

inlcusion in the Stockholm

Convention, Norman 2015,

EU HBM data available,

longest half-live in humans

(8.5-30 years)

6 https://echa.europa.eu/documents/10162/13641/rest_pfcas_axvreport_sps-013246-17_en.pdf/ab1c11b0-4ec9-4287-b9c5-

32cb98607152

https://echa.europa.eu/documents/10162/13641/rest_pfcas_axvreport_sps-013246-17_en.pdf/ab1c11b0-4ec9-4287-b9c5-32cb98607152

https://echa.europa.eu/documents/10162/13641/rest_pfcas_axvreport_sps-013246-17_en.pdf/ab1c11b0-4ec9-4287-b9c5-32cb98607152

[13]

FOSA, PFOSA Perfluoroctylsulfonamide;

Perfluorooctanesulfonic acid

amide or

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8

-Heptadecafluoro-1-

octanesulfonamide (IUPAC)

754-91-6

PFOS-related substance;

POP Regulation (EG) No.

757/2010, OSH legislation

(Council Directive 98/24/EC

on protection of health and

safety of workers),

environmental legislation

(Seveso, Directive

2012/18/EU), self


Skin irrit. 2, Eye irrit. 2,

STOT SE 3), Norman 2011,

some (but not sufficient) EU

HBM data available (e.g.

Haug et al., 2009), other

non-EU HBM data (e.g. Jin

et al., 2016)

n-MeFOSA

N-methylperfluoro-1

octanesulphonamide

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8

-Heptadecafluoro-N-methyl-1-


31506-32-8



757/2010, PIC Regulation,

Norman 2011, some (but not

sufficient) EU HBM data

available (e.g. Bartolomé et

al., 2017), other non-EU

HBM data (e.g. Jin et al.,

2016; Yeung and Mabury,

2016)

N-Et-FOSAA, Et-

PFOSA-AcOH, Et-

FOSAA

N-Ethyl-

perfluorooctanesulfonamido

acetic acid; N-ethyl-

perfluorooctane

sulfonamidoacetate or N-ethyl-

N-[(1,1,2,2,3,3,4,4,5,5,6,6,7,

7,8,8,8-heptadecafluoro

octyl)sulfonyl]-glycine (IUPAC)

2991-50-6

PFOS-related substance,

transformation product, POP

Regulation (EG) No.

757/2010, its salts may be

marketed under different

trade names, may be marker

of food or consumer

exposures, Norman 2015,

limited EU HBM data

available (ELFE study –

serum samples), other non-

EU HBM data (e.g. Kato et

al., 2014)

N-EtFOSA,

SULFLURAMID

N-ethylperfluoro-1-

octanesulphonamide or N-

Ethyl-

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8

-heptadecafluoro-1-


4151-50-2



757/2010, PIC Regulation,

environmental legislation

(Seveso, Directive

2012/18/EU), self

classification (Acute tox. 4),

Norman 2011, investigated

in human samples but not

[14]

detected (Jin et al., 2016,

Miyake et al., 2007, Yeung

and Mabury, 2016), detected

in indoor dust and air

samples (Gebbink et al.,

2015)

N-EtFOSE

N-ethyl-perfluorooctane

sulphonamidoethanol; N-Ethyl-

N-(2-

hydroxyethyl)perfluorooctanesul

fonamide or N-Ethyl-

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8

-heptadecafluoro-N-(2-

hydroxyethyl)-1-


1691-99-2


POP Regulation (EU) No.

850/2004 idgF, PIC

Regulation, Norman 2011,

detected in indoor dust and

air samples (Gebbink et al.,

2015), quickly and

extensively metabolised to

PFOSA with an elimination

half-life of 16-20 h,

metabolites of N-EtFOSE

werde found in human

samples (Thayer and

Houlihan, 2002), HBM data

scarcely available

N-MeFOSE

N-methyl

perfluorooctanesulfonamidoeth

anol or

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8

-heptadecafluoro-N-(2-

hydroxyethyl)-N-methyloctane-

1-sulfonamide (IUPAC)

24448-09-7


POP Regulation (EU) No.

850/2004 idgF, PIC

Regulation, detected in

indoor dust and air samples

(Gebbink et al., 2015), no

HBM data available at

current knowledge

8:2 diPAP

polyfluoroalkyl phosphoric acid

diesters,

Bis(3,3,4,4,5,5,6,6,7,7,8,8,9,9,1

0,10,10-heptadecafluorodecyl)

hydrogen phosphate

678-41-1

PFOA-related substance,

REACH Annex XVII


2017/1000), Norman 2015,

Priority HBM List California,

limited EU HBM data

available (Yeung et al.,

2013a, 2013b); other non-

EU HBM data (e.g. Lee and

Mabury, 2011; Yeung and

Mabury, 2016)

6:2/8:2 diPAP 6:2/8:2 polyfluoroalkyl

phosphoric acid diesters 943913-15-3


REACH Annex XVII


2017/1000), Priority HBM

List California, no HBM data

available at current

knowledge

[15]

8:2 monoPAP 8:2 polyfluoroalkyl phosphoric

acid monoester 57678-03-2


REACH Annex XVII


2017/1000), no HBM data


knowledge

B

ADONA

Ammonium 4,8-dioxa-3H-

perfluorononanoate

(ammonium 2,2,3 trifluor-3-

(1,1,2,2,3,3-hexafluoro-3-

trifluormethoxypropoxy),

propionate)

958445-44-8

Alternative to APFO,

possible PPARα antagonist,

use in food contact

material,according to EFSA

no risk under specific

conditions of use (EFSA,

2011 b) , CoRAP (suspected

PBT/vPvB, exposure of

environment, wide dispersive

use), highlighted by ECHA,

limited EU HBM data

available (e.g. Fromme et

al., 2017)

PFBA perfluoro-n-butanoic acid 375-22-4

REACH RMOA7, Annex III

(suspected P), OSH

legislation (Council Directive

98/24/EC on protection of

health and safety of

workers), self classification

(Skin corr. 1A, Eye dam. 1,

STOT SE 3, Metal corr. 1),

Norman 2015, highlighted by

ECHA, levels rising in

environment and human

tissues (Scheringer et al.,

2014), some (but not


available in plasma, serum,

breast milk8

PFPeA perfluoro-n-pentanoic acid 2706-90-3

REACH Annex III (suspected

P, skin irritant), OSH





(Skin corr. 1B, Metal corr. 1,


highlighted by ECHA, some

(but not sufficient) EU HBM

7 RMOA: Analysis of the most appropriate risk management option: https://echa.europa.eu/de/rmoa

8 e.g. Antignac et al., 2013; Schröter-Kermani et al., 2013; Sochorová et al., 2017

[16]

data available in plasma,

serum, urine9

PFHxA perfluoro-n-hexanoic acid 307-24-4

RMOA, REACH Annex III

(suspected P, C), PACT list

(PBT), OSH legislation



safety of workers), self

classification (Skin corr. 1B,

Metal corr. 1, Eye dam. 1,

Acute tox. 4), Norman 2011,

highlighted by ECHA, in

Spain higher levels were

found in liver samples (68-

141 ng/g) (Perez et al.,

2012), some (but not



whole blood, breast milk,

urine, liver10

PFHpA Perfluoro-n-heptanoic acid 375-85-9


B, P, C, acute tox via oral

route, toxic), OSH legislation





Skin corr. 1B, Metal corr. 1,


highlighted by ECHA, some


data available in serum,

plasma, whole blood, urine,

breast milk11

PFBS perfluoro-1-butanesulfonate 375-73-5

RMOA, PACT list, REACH

Annex III (suspected P, R),

OSH legislation (Council


protection of health and

safety of workers, Council

Directive 94/33/EC on the

protection of young people at

work), self classification

(Acute Tox. 4, Skin corr. 1B,

9 e.g. Hartmann et al., 2017; Schröter-Kermani et al., 2013; Sochorová et al., 2017

10 e.g. Antignac et al., 2013; Ericson et al., 2007; Glynn et al., 2012; Hartmann et al., 2017; Perez et al., 2012; Schröter-Kermani et al.,

2013; Sochorová et al., 2017 11

e.g. Antignac et al., 2013; Ericson et al., 2007; Glynn et al., 2012; Hartmann et al., 2017; Schröter-Kermani et al., 2013;

Umweltbundesamt, 2013) (unpublished report)

[17]

Metal corr. 1, Eye dam. 1),

highlighted by ECHA, ground

water contaminant, some


data available in serum,

whole blood, breast milk12

PFHpS perfluoro-heptanesulfonate 60270-55-5


B, P, C, R, toxic, acute tox

via oral route), self


Eye irrit. 2, STOT SE 3), EU

HBM data available

PFDS perfluoro-1-decanesulfonate 335-77-3


B, P, C, R, acute tox via oral

route), some (but not



breast milk, urine13

N-Me-PFOSA-

AcOH, Me-FOSAA

N-Methyl-perfluorooctane

sulfonamido acetic acid 2355-31-9

transformation product, may

be marker of food or

consumer exposures, limited


(ELFE study – serum

samples), other non-EU

HBM data (e.g. Kato et al.,

2014)

6:2 FTSA, H4PFOS,

THPFOS

3,3,4,4,5,5,6,6,7,7,8,8,8-

tridecafluorooctanesulphonic

acid, 6:2 fluorotelomer sulfonic

acid

27619-97-2


P, B, C, skin irritant), OSH



health and safety of workers,

Council Directive 94/33/EC

on the protection of young

people at work), Annex III


waste, self classification

(Skin corr. 1B, Eye dam. 1,

Acute tox. 4, STOT RE 2),

other non-EU HBM data

(Yeung and Mabury, 2016)

8:2 FTSA

3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10

,10-

heptadecafluorodecanesulphoni

c acid, 8:2 fluorotelomer 39108-34-4


P, C, skin irritant), Priority

HBM List California, other

(non-EU) HBM data (Yeung

12

e.g. Ericson et al., 2007; Glynn et al., 2012; Umweltbundesamt, 2013 (unpublished report) 13

e.g. Antignac et al., 2013; Hartmann et al., 2017; Haug et al., 2009; Schröter-Kermani et al., 2013; Umweltbundesamt, 2013

(unpublished report)

[18]

sulfonic acid and Mabury, 2016 – levels in

all human blood samples

below LOQ)

PFODA Perfluorostearic acid;

Perfluorooctadecanoic acid 16517-11-6


C, P), priority HBM List

California, limited EU HBM

data available (Gebbink et

al., 2015)

PfHxDA

Perfluoropalmitic acid,

Perfluoro-n-hexadecanoic acid

or

2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,1

0,10,11,11,12,12,13,13,14,14,1

5,15,16,16,16-

Hentriacontafluorohexadecanoi

c acid (IUPAC)

67905-19-5


P, B, C), Priority HBM List

California, no HBM data


knowledge

C

C

4:2 FTSA

4:2 fluorotelomer sulfonic acid,

3,3,4,4,5,5,6,6,6-Nonafluoro-1-

hexanesulfonic acid (IUPAC) 757124-72-4


no EU HBM data available at

current knowledge, other

non-EU HBM data (Yeung

and Mabury, 2016 – levels in

all human blood samples

below LOQ)

5:3 FTCA

7:3 FTCA

Fluorotelomer carboxylic acids 5:3 Fluorotelomer carboxylic acid

7:3 Fluorotelomer carboxylic

acid

-

Fluorotelomer metabolites,


detected in blood samples of

ski way technicans (Nilsson

et al., 2013), HBM data

scarcely available

6:2 FTUCA 8:2 FTUCA

10:2 FTUCA

Fluorotelomer unsaturated carboxylic acids 6:2 Fluorotelomer unsaturated carboxylic acid 8:2 Fluorotelomer unsaturated carboxylic acid

10:2 Fluorotelomer unsaturated

carboxylic acid

70887-88-6 70887-84-2

70887-94-4



detected in blood samples of

ski way technicans (Nilsson

et al., 2013), HBM data

scarcely available

PFECA (GenX)

Perfluoroether carbocylic acids for example:

Ammonium 2,3,3,3-tetrafluoro-

2-

(heptafluoropropoxy)propanoat

e (GenX) 62037-80-3

CoRAP (suspected


environment), OSH



health and safety of workers,

Council Directive 94/33/EC

on the protection of young

people at work), Annex III


waste, self classification

(Acute tox. 4, Skin corr. 1C,

[19]

Eye dam. 1, STOT SE 3,

Skin corr. 1B), Norman

2015, highlighted by ECHA,

no HBM data available at

current knowledge

PFECA

perfluoro-1,1-ethylene glycol, terminated with chlorohexafluoropropyloxy groups

Perfluoro[(2-ethyloxy-

ethoxy)acetic acid], ammonium

salt

908020-52-0

CoRAP (suspected


environment), resistent, not

easily to metabolise, maybe

bioaccumative, expected

increase in production and

use, partially used in food

contact materials, restriction

on use according EFSA, no

safety concern under the

respective conditions

identified (EFSA, 2011) no


current knowledge

6:2 FTMAC

Fluorotelomer methacrylates e.g.

3,3,4,4,5,5,6,6,7,7,8,8,8-

tridecafluorooctyl methacrylate

2144-53-8

CoRAP (potential endocrine

disrupter, suspected

PBT/vPvB, other hazard

based concern, exposure of


use), PACT list, OSH





(STOT RE 2, STOT SE 3,

Skin irrit. 2, Eye irrit. 2), fully

registered substance 100-

1.000 tonnes, suspected

endocrine disrupter, used for

polymer production, in

human blood propably only

metabolites detectable

(FTOH, FTCA, FTUCAs), no


current knowledge

6:2 FTAC 8:2 FTAC

10:2 FTAC

Fluorotelomer acrylates e.g. 6:2 Fluorotelomer acrylate (8:2 Fluorotelomer acrylate 10:2 Fluorotelomer acrylate)

17527-29-6

CAS# 17527-29-6: CoRAP

(potential endocrine

disrupter, suspected




use), PACT list;

CAS# 27905-45-9 and CAS#

17741-60-5: REACH Annex

[20]

27905-45-9

17741-60-5

III (suspected P, C,

respiratory sensitiser, skin

irritant, skin sensitiser);

FTAC is a PFOA-related

compound;

used for polymer production,


in human blood probably

only metabolites detectable,


current knowledge

PfHxDA

Perfluoropalmitic acid,

Perfluoro-n-hexadecanoic acid

or

2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,1

0,10,11,11,12,12,13,13,14,14,1

5,15,16,16,16-

Hentriacontafluorohexadecanoi

c acid (IUPAC)

67905-19-5


P, B, C), Priority HBM List

California, no HBM data


knowledge

C4/C4 PFPiA Bis(nonafluorobutyl)phosphinic

acid

52299-25-9

CoRAP (suspected



environment), no HBM data


knowledge

8:2 FTOH 8:2 fluorotelomer alcohol 678-39-7

CLH proposal (Repr 1B),






Eye irrit. 2, STOT SE 3),

Norman 2011, no HBM data


knowledge

C6/C6 PFPiA Bis(perfluorohexyl)phosphinic

acid

40143-77-9 Limited HBM data available

(Human sera , single and

pooled donor sample 2009,

US : <1 - 50.2 ng/Land <1 -

201.4 ng/L (median) Lee &

Mabury (2011)

C6/C8 PFPiA Bis(perfluorohexyloctyl)phosphi

nic acid

610800-34-5 Priority HBM List California,

Limited HBM data available

(Human serasingle and


US : <1 - 60.9 ng/L and <1 -

283.4 ng/L(median) Lee &

[21]

Mabury (2011)

C8/C8 PFPiA Bis(perfluorooctyl)phosphinic

acid

40143-79-1 Limited HBM data available

(Human sera , single and


US : <1 - 22.2 ng/Land <1 -

50.7 ng/L (median) Lee &

Mabury (2011)

D

HFPO hexafluoropropylene oxide 220182-27-4

Highlighted by ECHA, no


current knowledge

PFCHS

Cyclic PFSA e.g Cyclohexanesulfonic acid undecafluoro-, potassium salt Cyclohexanesulfonic acid, nonafluorobis(trifluoromethyl)-, potassium salt

Perfluoro-4-ethylcyclohexane

sulfonate

3107-18-4 68156-01-4 335-24-0

CAS# 3107-18-4, CAS#

68156-01-4, CAS# 335-24-0:


C, P) ;


current knowledge

6:2/8:2 diPAP 6:2/8:2 polyfluoroalkyl

phosphoric acid diesters 943913-15-3


REACH Annex XVII


2017/1000), Priority HBM

List California, no HBM data


knowledge

8:2 monoPAP 8:2 polyfluoroalkyl phosphoric

acid monoester

57678-03-2


REACH Annex XVII


2017/1000), no HBM data


knowledge

PFOPA

Perfluorooctylphosphonic acid,

2-(Perfluorohexyl)ethyl]

phosphonic acid

252237-40-4

Sodium salt REACH

registration (ECHA, 2017)

High environmental

exposure, Priority HBM List

California, limited HBM data

available, not detected in US

human sera in Lee &Mabury

(2011)

Perfluorinated

Siloxane

Trimethoxy(1H,1H,2H,2H-

heptadecafluorodecyl)silane 83048-65-1




safety of workers, Council

Directive 94/33/EC on the

protection of young people at

work), Annex III Directive

[22]

2008/98/EC on waste, self


Eye irrit. 2, Skin corr. 1B), no


current knowledge

FL16.119 N-(2-methylcyclohexyl)-

2,3,4,5,6-pentafluorobenzamide

1003050-32-

5

more information on use and

use levels needed EFSA

(CEF panel, 2017)

Other health hazard, no


current knowledge

E

6:2 FTCA 8:2 FTCA

10:2 FTCA

Fluorotelomer carboxylic acids: 6:2 Fluorotelomer carboxylic acid, 8:2 Fluorotelomer carboxylic acid

10:2 Fluorotelomer carboxylic

acid

53826-12-3 27854-31-5 53826-13-4




current knowledge

PFECA

Perfluoro-1,2-propylene glycol and perfluoro-1,1-ethylene glycol, terminated with chlorohexafluoropropyloxy groups

Perfluoro[(2-ethyloxy-

ethoxy)acetic acid], ammonium

salt

329238-24-6

resistent, not easily to

metabolise, maybe

bioaccumative, expected

increase in production and

use, partially used in food

contact materials, restriction

on use according EFSA, no

safety concern under defined

conditions (EFSA, 2010) no


current knowledge

FBSA Perflurobutane sulfonamide 30334-69-1

Alternative to PFOS,

tranformation product,

recently detected in biota

(fish) (Cu et al., 2016)

MeFBSE N-Methyl perfluorobutane-

sulfonamidoethanol

34454-97-2

REACH, registered

substance, Intermediate;

Surfactants; Repellents for

porous hard surfaces; Tile

grout additive, Registered 12

– 100 t/y

6:2 PAP 6:2 polyfluoroalkyl phosphoric

acid monoesters 57678-01-0



current knowledge

6:2 diPAP 6:2 polyfluoroalkyl phosphoric

acid diesters 57677-95-9



current knowledge

[23]

PFHxPA Perfluorohexylphosphonic acid 40143-76-8

high environmental

exposure, Priority HBM List

California, not detected in

US human sera in Lee

&Mabury (2011) limited HBM

data available

PFDPA Perfluorodecylphosphonic acid 52299-26-0


not detected in US human

sera in Lee &Mabury (2011)

limited HBM data available

C8/C10 PFPiA Bis(perfluorooctyldecyl)phosphi

nic acid 500776-81-8


current knowledge

Denum SH

Poly[oxy(1,1,2,2,3,3-hexafluoro-

1,3-propanediyl)],a-(2-carboxy-

1,1,2,2-tetrafluoroethyl)-w-

(1,1,2,2,3,3,3-

heptafluoropropoxy)-

120895-92-3 no HBM data available at

current knowledge

Krytox Krytox-H 60164-51-4 no HBM data available at

current knowledge

Fomblin Z-DIAC, Fomblin Z-DIAC,

bis(pentafluorophenyl) ester 97462-40-1


current knowledge

- C3; C15-C20 PFCA - no HBM data available at

current knowledge

- C3, C15-C20 PFSA - no HBM data available at

current knowledge

TFEE-5

Polyfluoro-5,8,11,14-

tetrakis(polyfluoralkyl)-

polyoxaalkane

-

CoRap, suspected PBT

polymers: PTFE PVDF PVF TFE

HFP

Teflon: Polytetrafluoroethylene 1,1 Difloroethene (PVDF) Polyvinyl fluorine (PVF) Tetrafluoroethylene (TFE)

Hexafluoropropylene (HFP)

9002-84-0 24937-79-9 24981-14-4 116-14-3

116-15-4

More research on polymers

Building blocks:

CAS# 9002-84-0: REACH

Annex III (suspected CMR);

CAS# 24937-79-9: REACH

Annex III (suspected P, M,

hazardous to aquatic

environment);

CAS# 24981-14-4: -

CAS# 116-14-3: PACT list

(CMR);

CAS# 116-15-4: CLH (Press.

Gas, Acute Tox. 4, STOT SE

3), CoRAP (suspected CMR,

high (aggregated) tonnage);

[24]

production of toxic products

if overheated; production of

ultrafine particles by

degradation; lung

inflammation (PTFE), toxic

monomers (PTFE); no HBM

data available at current

knowledge

[25]

4. Policy-related questions

1. What is the current exposure of the EU population to PFASs and do they exceed Guidance values (reference and HBM values), where available?

2. Are there differences in exposure of the EU population to regulated and non-regulated PFASs?

3. Has restriction of PFOS according to the POP Regulation led to a reduction in exposure, especially for children?

4. Is exposure driven by diet, consumer exposure, occupation or environmental contamination?

5. Which areas and environmental media in Europe are contaminated with PFASs?

6. How can this feed into an assessment of the TDI for PFOS and PFOA set by EFSA?

7. What is the impact of a pending 2016 ECHA decision to restrict the manufacturing, marketing and use of PFOA under REACH?

8. Is it important to eliminate legacy PFASs from material cycles (i.e. waste electronic equipment) when implementing a circular economy in order to protect human health?

9. Can differences in PFASs profiles be observed in different population groups and time periods?

10. What are the PFASs levels and health effects in vulnerable population groups?

11. How can mixture effects of environmental and human PFASs mixtures present to date be estimated?

12. How can PFAS substances of relevance for human exposure and health be identified having in mind that more than 3000 substances are at the market?

13. How can identification and assessment (including data on (potential) adverse effects on human health and the environment) of alternatives currently hampered by CBI (Confidential Business Information) be facilitated?

14. How much are HBM values dependent on host characteristics and does this have implications for identifying vulnerable groups?

[26]

5. Research Activities to be undertaken

Table 2: Listing of research activities proposed to answer the policy questions summed up in

1.3

Policy

question

Substance Available knowledge

related to policy question

Knowledge gaps / Activities needed to

answer policy question

1 CAT A and

B

substances

Alternatives to PFOS (e.g.

PfHxS, PFBS) are detected

more frequently and in

increasing concentrations

Proceed with collecting, combining, harmonizing

and comparing existing exposure data on PFASs

WP 10

1 PFOS and

PFOA

There are ongoing discussions

on the appropriate Point of

Departure for derivation of

DNELs respective HBM values

for PFOS and PFOA; values

differ among orders of

magnitude

Compare PFOS and PFOA exposure values with

the newly derived HBM values from the German

HBM Commission and the upcoming EFSA health

guideline values, develop health based HBM4EU

guidance values values for PFOS and PFOA

WP 5

1 CAT A and

B

substances

Within year one (2017)

assessment of the so far

conducted PFASs studies will

make it possible to answer this

question, at least for some of

the substances.

For others targeted studies

should be performed.

Based on the results a detailed data gap analysis

should be performed, taking the respective human

health related endpoints into consideration in order

to address the question if health based guidelines

are met or not. In order to specifically address

health endpoints where currently insufficient data

are available study protocols should include

measurement of transaminases, cholesterol,

immune parameters and thyroid hormones.

Mixture effects should be considered, taking the

similar mode of action for certain substances into

consideration. Uncertainty regarding the total

PFASs exposure has to be considered.

WP 5, 8,9,10,15

2 CAT A and

B probably

C

substances

Within the first year

assessment differences in

exposure will be documented.

To date PFOS and PFOA are

most probably still the

substances occurring in the

highest concentrations in

serum in Europe and

elsewhere, however

concentrations of alternatives

– e.g. long chain compounds

(such as PFNA and PfHXS) or

short chain PFAS (such as

New targeted studies identifying a multitude of

PFASs in human blood and urine including newly

developed methods such as TOF or oxidisable

fractions should be planned and performed, in

order to be able to quantify also the so far

unidentified compounds. Analyses should be

further complemented by measurement of

transaminases, cholesterol, immune parameters

and thyroid hormones.

Development of TOF and oxidisabel fraction

methods should be validated and harmonised in

order to integrate them in planned and ongoing

[27]

PFBS, PFBA) are increasing. studies

WP 8,9, WP14 ( effect biomarkers)

3 PFOS The effectiveness evaluation

under the UNEP Stockholm

Convention concluded that for

human matrices from Western

Europe, Canada, Australia and

Asia-Pacific countries levels

seem gradually declining.

It will most probably turn out

that data on PFAS exposure in

children is currently

underrepresented; most

studies performed within

Europe are from adult

populations with the

exceptions of birth cohorts.

Exposure of children to PFASs should be

investigated, complemented by measurement of

transaminases, cholesterol, immune parameters

and thyroid hormones.

WP 8,9,10 and WP14 ( effect biomarkers)

4 Cat A and B

substances

Long chain PFASs exposure is

presumed to be via diet;

contribution of food additives

and flavourings is so far not

sufficiently investigated. Also

knowledge on the exposure to

short chain PFASs via diet

(e.g. crops and vegetables)

and drinking water is scarce.

Further, information on

exposure via various

consumer product has to be

considered.

All new studies performed within HBM4EU

targeting PFASs should include a detailed

questionnaires based on current knowledge on

exposure pathways. Therefore a PFASs related

questionnaire should be developed.

WP 8,9

Link with dietary surveys if possible (WP11)

External modelling: WP12

5 Cat A and B

substances

Currently there are several hot

spots known in different

countries (e.g. Germany,

Sweden, Italy, Spain,

Netherlands). It can be

assumed that hot spots exist

also in the majority of the

European and associated

countries.

A questionnaire should be developed based on the

knowledge existing from known cases (e.g. reason

for contamination, facility, substances related to the

respective case, production or use volume, area

contaminated). The questionnaire could be sent out

to NHCPs in order to get an overview on other

known or suspected cases.

“Bioambient.es” project (IISCIII, Spain) could be

taken into account.

http://democophes.blogs.isciii.es/2012/04/04/bioam

bient-es/.

http://democophes.blogs.isciii.es/category/biomonit

orizacion-espana/

If so, I guess that further information regarding this

activity have been (or will be) provided by IISCIII.

Exposure modelling in relation with HBMdata

http://democophes.blogs.isciii.es/2012/04/04/bioambient-es/

http://democophes.blogs.isciii.es/2012/04/04/bioambient-es/

[28]

(WP12)

6 Cat A and B

Substances

The EFSA opinion will be

published in 2018. As working

group members are involved in

HBM4EU, information

exchange can be expected.

The detailed EFSA assessment shall be used

within HBM4EU for defining data gaps and refining

research questions. Based on previous information

exchange and discussion among HBM4EU

partners it is clear that there are several questions

on human health that have to date not been

sufficiently addressed due to relatively small size of

many previous studies. Combining several

comparable studies will allow for more robust

assessment of health outcomes in terms or broader

exposure range and examination of rare health

outcomes which individual studies have been

underpowered to address (including low birth

weight, pregnancy complications.

WP 13

7 PFOA and

related

substances

The restriction is expected to

lead to declining levels of

PFOA

The identification, assessment and monitoring of

alternatives is of importance.

WP 4, 5

WP 10 time trend data analysis

8 Cat A

Substances

According to experts in

different fields it is anticipated

to eliminate legacy PFASs

from waste streams.

It is not clear whether this question can be tackled

within HBM4EU; Research on the life cycle of

products may identify potential exposure routes.

[Studies near landfields could clarify if PFASs

exposure occurs.]

WP 7,8,9

9 Cat A, B, C

substances

To identify differences in the exposure levels of

unregulated and regulated Cat. A substances (and

Cat B and C substances if data are available)

between countries and time periods, and to identify

the main reasons for differences in

exposure.*Population groups: living in different

areas and divided by sex and gender.

WP 10, 12

10 Cat A , B

and C

substances

As PFASs exposure pattern

are changing current exposure

of vulnerable populations

needs to be investigated.

Current exposure levels in vulnerable populations

need to be investigated, preferable with methods,

which allow identifying Cat A , B and C substances

as well as the total PFASs burden.

*Vulnerable population: children (high half lives of

PFAS) and those affected by health effects linked

to the potential PFAS exposure.

WP 8,9

WP13 exposure effect studies

10 Cat A Study how PFASs affect AOPs that lead to critical

[29]

substances endpoints in humans such as effects on liver and

thyroid, developmental toxicity, immunotoxicity and

non carcinogenic toxicogenicity. Prenatal exposure

is suspected to cause reduced birth weight and or

small for gestational age, suggesting unborn as

vulnerable exposure group.

WP 13

11 Mixture of

substances

Identificatio

n of Cat E

substances

To address questions related to mixture effects

(due to similar mode of action and potential over-

additive effects of combined exposures): e.g.

peroxisome proliferation, mitochondrial toxicity,

cytotoxicity, and transcriptome profiles of key

metabolic pathways of the liver, immunotoxicity

reproductive, developmental and carcinogenic

effects and also address multipollutant (PFASs)

exposure in relation to adverse health effects in

epidemiological studies

WP 13, WP15

12 Cat D and E

substances

What compounds should be

prioritized for further

information regarding

exposure and/or toxicity? How

can use and risk information

be combined to identify and

prioritize knowledge gaps for

further studies?

Identification of compounds to be prioritized for

further information on exposure and/or toxicity to

be measured in HBM studies

WP 4,5

Identify lead chemicals in mixtures of PFAs

WP14 and WP15

Design new studies that measure these exposure

biomarkers WP8

14 PFOA/PFOS There is evidence of wide

variability in half life, with

gender, renal function and

genetics shown to explain

some of the variation and HBM

levels.

Taking into consideration the differences in

toxicokinetics of linear and branched isomers, fuller

characterization of role of gender, existing disease

use of medicines and other causes affecting

measured HBM in serum

WP8 and WP10

[30]

6. Results Report

In Year 2 (M18) a short overview of the results achieved within the HBM4EU programme shall be

depicted here. Please, briefly state the main results answering the corresponding policy questions

in a general understandably manner.

Table 3: Short overview of results of the activities carried out within HBM4EU to answer the policy

questions with reference to corresponding deliverables

Policy Question No.

(keyword)

Short Summary of Results

If there is a Deliverable you extracted the results from, please mention it

[31]

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